Background: Lung cancers are often driven by mutant epidermal growth factor receptor (mtEGFR). While EGFR tyrosine kinase activity inhibitors (TKI) have shown effectiveness, within 9-13 months all patients develop resistance including to 3rd generation TKI - Osimertinib. These patients do not have any approved therapy options, therefore, there is an urgent need to develop a novel agent that functions independently of kinase function. DGD1202, a first-in-class, novel, orally bioavailable, small molecule that inhibits EGFR dimerization, induces degradation of EGFR and selectively kills TKI resistant NSCLC tumors. Objective: We and others have shown that the degradation of mutant EGFR protein has a profound effect on cancer cell survival. Thus, we hypothesized that a drug which induces degradation of mtEGFR independent of the ATP binding domain will result in selective activity. Our objective is to evaluate the therapeutic potential of DGD1202 in a panel of lung cancer cells lines, xenografts, and PDXs derived from lung cancer patients containing mtEGFR who have undergone treatment with a TKI. Specific Aims: We propose to evaluate the specificity and potency of DGD1202 against TKI-resistant lung cancer cells and xenografts. Aim 1 is to determine the in vitro efficacy of DGD1202 against a panel of EGFR driven, including osimertinib-resistant, cancer cell lines relative to normal cells. Aim 2 is to conduct in vivo pharmacokinetic (PK) and pharmacodynamic (PD) analyses to assess drug exposure and determine the effect on the target. Aim 3 is to determine the overall therapeutic efficacy and long-term safety of DGD1202 in vivo. We hypothesize that treatment with DGD1202 will induce EGFR degradation preferentially in tumor cells driven by mtEGFR and that EGFR degradation will correlate with the overall response. Study Design: We will screen DGD1202 alongside osimertinib in a series of lung cancer lines. The resulting response will be then correlated with effect on EGFR degradation. We also propose to determine in vivo PK and PD studies both with a single and with fractionated dosing to determine the optimum bioavailability. Using the optimized dose and schedule, we will assess effects on EGFR protein against a panel mtEGFR-driven and osimertinib resistant lung cancer xenograft and PDX models. The long-term safety will be assessed in immune competent mice. Standard statistical models will be used to compare the response to treatment and how it correlates with effects on EGFR. Impact: We anticipate that our approach will open a new way to target EGFR and, more broadly, to develop therapeutics to selectively target mutated proteins to degradation. The knowledge gained from in vivo tumor models will provide a rationale for the use of this class of molecules in future clinical studies.